PROJECT SUMMARY/ABSTRACT Building on her rich clinical background in addiction treatment, Dr. Keren Bachi, the candidate, aspires to become a cross-disciplinary independent investigator in an area of critical importance within drug addiction: the neuro-immune biomarkers underlying adult social cognitive function (mentalizing; the ability to understand the mental states of others) as associated with exposure to early life stress. Drug addicted individuals frequently experience social stress (e.g., childhood maltreatment, poverty) which may shape neural and physiological responses to social interactions and exacerbate illness risk (e.g., craving, relapse). Training will center on neuro-immune-environment systems approach to drug addiction, with mentorship in neuroimaging of human addiction (primary mentor Dr. Goldstein), immune dysregulation in psychiatry (Dr. Gabbay), neuroinflammation (Dr. Russo), advanced biostatistics (Mr. Weinberg), immunologic assessment (Dr. Kim-Schulze), social cognition (Dr. Moeller), and mechanisms linking stress, immune adaptations, and effects on brain function in addictive behaviors (Dr. Sinha). Goals will be accomplished through didactic training primarily at the Icahn School of Medicine at Mount Sinai, conferences, and mainly by the study of: (I) characterizing the behavioral and neural correlates of deficits in mentalizing in cocaine addicted individuals vs. matched healthy controls, using a well-validated functional magnetic resonance imaging paradigm that robustly activates the mentalizing network; (II) comparing inflammation between the two study groups, using an immune-blood-profile previously associated with cocaine use, but here examined for the first time vis--vis mentalizing and childhood maltreatment; and (III) discerning whether inflammation markers mediate the relationships between childhood trauma with altered neural engagement/behavior during the mentalizing task. While neuroimaging allows for spatially specific determination of brain activity, immune biomarkers enable detection of molecular and cellular-pathways, and their join study would facilitate identification of neuro- immune contributions to core deficits in addiction. Furthermore, testing for a contribution of biographic adversity-history may enable the grounding of the neural and physiological findings in identifiable (and potentially preventable) long-lasting effects of social-environmental stress. Future efforts could capitalize on the putative mediating effects of inflammation, to develop novel treatments in drug addiction incorporating immunomodulatory or anti-inflammatory drugs, which notably have been shown to enhance cognition in other psychiatric patients. Enhancement of social cognition (mentalizing) could augment treatment success and prevent relapse in addiction. Finally, social stress management interventions and prevention efforts could potentially most optimally be deployed in those with severe childhood maltreatment. The experience, and data gained from this study will position the candidate to pursue future NIH funding to build this line of research and develop novel treatments in drug addiction.